5-methyl-1,2,4-oxadiazol-3-yl compounds

ABSTRACT

The present invention provides a compound of Formula I: 
                         
or a pharmaceutically acceptable salt thereof, and the use of compounds of Formula I for treatment of neurodegenerative diseases and disorders, such as Alzheimer&#39;s disease.

The present invention relates to novel 5-methyl-1,2,4-oxadiazol-3-ylcompounds, to pharmaceutical compositions comprising the compounds, tomethods of using the compounds to treat physiological disorders, and tointermediates and processes useful in the synthesis of the compounds.

The present invention is in the field of treatment of Alzheimer'sdisease, progressive supranuclear palsy (PSP) and other diseases anddisorders involving tau-mediated neurodegeneration, known collectivelyas tauopathies.

Alzheimer's disease is a devastating neurodegenerative disorder thataffects millions of patients worldwide. In view of the currentlyapproved agents on the market which afford only transient, symptomaticbenefits to the patient, there is a significant unmet need in thetreatment of Alzheimer's disease.

The oligomerization of the microtubule-associated protein tau intofilamentous structures such as paired helical filaments (PHFs) andstraight or twisted filaments, which give rise to neurofibrillarytangles (NFTs) and neuropil threads (NTs), is one of the definingpathological features of Alzheimer's disease and other tauopathies. Thenumber of NFTs in the brains of individuals with Alzheimer's disease hasbeen found to correlate closely with the severity of the disease,suggesting tau has a key role in neuronal dysfunction andneurodegeneration (Nelson et al., J Neuropathol Exp Neurol., 71(5),362-381(2012)). Tau pathology has been shown to correlate with diseaseduration in PSP; cases with a more aggressive disease course have ahigher tau burden than cases with a slower progression. (Williams etal., Brain, 130, 1566-76 (2007)).

Recent studies (Yuzwa et al., Nat Chem Biol, 4(8), 483-490 (2008))support the therapeutic potential of O-GlcNAcase (OGA) inhibitors tolimit tau hyperphosphorylation and aggregation into pathological tau forthe treatment of Alzheimer's disease and related tau-mediatedneurodegeneration disorders. Specifically, the OGA inhibitor Thiamet-Ghas been linked in slowing motor neuron loss in the JNPL3 tau mousemodel (Yuzwa et al., Nat Chem Biol, 8, 393-399 (2012)) and to areduction in tau pathology and dystrophic neurites in the Tg4510 taumouse model (Graham et al., Neuropharmacology, 79, 307-313 (2014)).Accordingly, OGA inhibitors are recognized as a valid therapeuticapproach to reduce the accumulation of hyperphosphorylated, pathologicalforms of tau, such as NFTs and NTs.

U.S. Pat. No. 9,120,781 discloses hexahydrobenzooxazole andhexahydrobenzothiazole derivatives which possess OGA inhibitory activityand are further disclosed as useful in treating diseases and disordersrelated to deficiency or overexpression of OGA, and/or accumulation ordeficiency of 2-acetamido-2-deoxy-5ß-D-glucopyranoside (O-GlcNAc). Inaddition, US 2016/0031871 discloses certain glycosidase inhibitors fortreating Alzheimer's disease.

OGA inhibitors that are brain penetrant are desired to providetreatments for tau-mediated neurodegeneration disorders, such asAlzheimer's disease and PSP. The present invention provides certainnovel compounds that are inhibitors of OGA.

Accordingly, the present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a compound of Formula Ia:

or a pharmaceutically acceptable salt thereof.

The present invention also provides a method of treating Alzheimer'sdisease in a patient in need of such treatment, comprising administeringto the patient an effective amount of a compound of Formulas I or Ia, ora pharmaceutically acceptable salt thereof.

The present invention further provides a method of treating theprogression of mild cognitive impairment to Alzheimer's disease in apatient in need of such treatment, comprising administering to thepatient an effective amount of a compound of Formulas I or Ia, or apharmaceutically acceptable salt thereof.

The present invention also provides a method of treating progressivesupranuclear palsy in a patient in need of such treatment, comprisingadministering to the patient an effective amount of a compound ofFormulas I or Ia, or a pharmaceutically acceptable salt thereof. Thepresent invention also provides a method of treating tau-mediatedneurodegenerative disorders in a patient, comprising administering to apatient in need of such treatment an effective amount of a compound ofFormulas I or Ia, or a pharmaceutically acceptable salt thereof.

Furthermore, this invention provides a compound of Formulas I or Ia, ora pharmaceutically acceptable salt thereof for use in therapy, inparticular for use in the treatment of Alzheimer's disease or for use inpreventing the progression of mild cognitive impairment to Alzheimer'sdisease. In addition, this invention provides a compound of Formulas Ior Ia, or a pharmaceutically acceptable salt thereof for use in thetreatment of progressive supranuclear palsy. The invention also providesa compound of Formulas I or Ia, or a pharmaceutically acceptable saltthereof for use in treating tau-mediated neurodegenerative disorders.

Even furthermore, this invention provides the use of a compound ofFormulas I or Ia, or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for the treatment of Alzheimer's disease orfor preventing the progression of mild cognitive impairment toAlzheimer's disease. In addition, this invention provides the use of acompound of Formulas I or Ia, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for the treatment ofprogressive supranuclear palsy. The invention also provides the use of acompound of Formulas I or Ia, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for treating tau-mediatedneurodegenerative disorders.

The invention further provides a pharmaceutical composition, comprisinga compound of Formulas I or Ia, or a pharmaceutically acceptable saltthereof, with one or more pharmaceutically acceptable carriers,diluents, or excipients. The invention further provides a process forpreparing a pharmaceutical composition, comprising admixing a compoundof Formulas I or Ia, or a pharmaceutically acceptable salt thereof, withone or more pharmaceutically acceptable carriers, diluents, orexcipients. This invention also encompasses novel intermediates andprocesses for the synthesis of the compounds of Formulas I and Ia.

Mild cognitive impairment has been defined as a potential prodromalphase of dementia associated with Alzheimer's disease based on clinicalpresentation and on progression of patients exhibiting mild cognitiveimpairment to Alzheimer's dementia over time. The term “preventing theprogression of mild cognitive impairment to Alzheimer's disease”includes restraining, slowing, stopping, or reversing the progression ofmild cognitive impairment to Alzheimer's disease in a patient.

As used herein, the terms “treating” or “to treat” includes restraining,slowing, stopping, or reversing the progression or severity of anexisting symptom or disorder.

As used herein, the term “patient” refers to a human.

As used herein, the term “effective amount” refers to the amount or doseof compound of the invention, or a pharmaceutically acceptable saltthereof which, upon single or multiple dose administration to thepatient, provides the desired effect in the patient under diagnosis ortreatment.

An effective amount can be readily determined by one skilled in the artby the use of known techniques and by observing results obtained underanalogous circumstances. In determining the effective amount for apatient, a number of factors are considered, including, but not limitedto: the species of patient; its size, age, and general health; thespecific disease or disorder involved; the degree of or involvement orthe severity of the disease or disorder; the response of the individualpatient; the particular compound administered; the mode ofadministration; the bioavailability characteristics of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

The compounds of the present invention are generally effective over awide dosage range. For example, dosages per day normally fall within therange of about 0.1 to about 15 mg/kg of body weight. In some instancesdosage levels below the lower limit of the aforesaid range may be morethan adequate, while in other cases still larger doses may be employedwith acceptable side effects, and therefore the above dosage range isnot intended to limit the scope of the invention in any way.

The compounds of the present invention are preferably formulated aspharmaceutical compositions administered by any route which makes thecompound bioavailable, including oral and transdermal routes. Mostpreferably, such compositions are for oral administration. Suchpharmaceutical compositions and processes for preparing same are wellknown in the art (See, e.g., Remington: The Science and Practice ofPharmacy, L. V. Allen, Editor, 22^(nd) Edition, Pharmaceutical Press,2012).

The compounds of Formulas I and Ia, or pharmaceutically acceptable saltsthereof are particularly useful in the treatment methods of theinvention, but certain configurations are preferred. The followingparagraphs describe such preferred configurations. It will be understoodthat these preferences are applicable both to the treatment methods andto the compounds of the invention.

Compounds of the present invention include:

and pharmaceutically acceptable salts thereof.

The compound of Formula I wherein the methyl and oxygen substituents onthe piperidine ring are in the cis or trans configuration, orpharmaceutically acceptable salt thereof, are included within the scopeof the invention, with the cis configuration being preferred. Forexample, one of ordinary skill in the art will appreciate that themethyl at position 2 is in the cis configuration relative to the oxygenat position 4 as shown in Scheme A below:

In addition, one of ordinary skill in the art will appreciate that themethyl at position 2 is in the trans configuration relative to theoxygen at position 4 as shown in Scheme B below:

Compounds wherein the chiral center at position 2 of piperidine ring isin the S-configuration are further preferred. Although the presentinvention contemplates all individual enantiomers and diasteromers, aswell as mixtures of the enantiomers of said compounds, includingracemates, the compounds with the absolute configuration as set forthbelow are particularly preferred:

N-[4-fluoro-5-[[(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamide,and pharmaceutically acceptable salts thereof; and

N-[4-fluoro-5-[[(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamideare particularly preferred.

The crystalline form ofN-[4-fluoro-5-[[(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamideis especially preferred. The crystalline form ofN-[4-fluoro-5-[[(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamidewhich is characterized by a peak in the X-ray powder diffractionspectrum at diffraction angle 2-theta of 12.1° in combination with oneor more peaks selected from the group consisting of 15.3°, 21.6°, 22.2°,22.7°, 23.5°, 24.3°, and 26.8°, with a tolerance for the diffractionangles of 0.2 degrees, is further preferred.

Individual isomers, enantiomers, and diastereomers may be separated orresolved by one of ordinary skill in the art at any convenient point inthe synthesis of compounds of the invention, by methods such asselective crystallization techniques or chiral chromatography (See forexample, J. Jacques, et al., “Enantiomers, Racemates, and Resolutions”,John Wiley and Sons, Inc., 1981, and E. L. Eliel and S. H. Wilen,“Stereochemistry of Organic Compounds”, Wiley-Interscience, 1994).

A pharmaceutically acceptable salt of the compounds of the invention canbe formed, for example, by reaction of an appropriate free base of acompound of the invention and an appropriate pharmaceutically acceptableacid in a suitable solvent under standard conditions well known in theart. The formation of such salts is well known and appreciated in theart. See, for example, Gould, P. L., “Salt selection for basic drugs,”International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin, R.J., et al. “Salt Selection and Optimization Procedures forPharmaceutical New Chemical Entities,” Organic Process Research andDevelopment, 4: 427-435 (2000); and Berge, S. M., et al.,“Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 66: 1-19,(1977).

The compounds of the present invention, or salts thereof, may beprepared by a variety of procedures known to one of ordinary skill inthe art, some of which are illustrated in the schemes, preparations, andexamples below. One of ordinary skill in the art recognizes that thespecific synthetic steps for each of the routes described may becombined in different ways, or in conjunction with steps from differentschemes, to prepare compounds of the invention, or salts thereof. Theproducts of each step in the schemes below can be recovered byconventional methods well known in the art, including extraction,evaporation, precipitation, chromatography, filtration, trituration, andcrystallization. In the schemes below, all substituents unless otherwiseindicated, are as previously defined. The reagents and startingmaterials are readily available to one of ordinary skill in the art.Without limiting the scope of the invention, the following schemes,preparations, and examples are provided to further illustrate theinvention. In addition, one of ordinary skill in the art appreciatesthat the compounds of Formulas Ia, Ib, Ic, and Id may be prepared byusing starting material with the corresponding stereochemicalconfiguration which can be prepared by one of skill in the art. Forexample, the Schemes below utilize starting materials with theconfiguration corresponding ultimately to Formula Ia.

Generally, a compound of Formula Ia may be prepared from a compound ofFormula II (Scheme 1). More specifically, a compound of Formula IIa isreductively alkylated with N-(4-fluoro-5-formylthiazol-2-yl)acetamide inthe presence of a suitable reducing agent such as sodiumtriacetoxyborohydride in a suitable solvent to provide a compound ofFormula Ia in a suitable solvent, such as ethyl acetate.N-(4-Fluoro-5-formylthiazol-2-yl)acetamide may be prepared by methodsknow in the chemical arts as well as methods provided in the followingPreparations and Examples.

A compound of Formula IIa may be prepared from a compound of FormulaIIIa where Pg is a suitable amine protecting group. More specifically, acompound of Formula IIa where Pg is tert-butyl carboxylate (t-BOC) isreacted with an acid such as hydrochloric acid or trifluoroacetic acidin a suitable solvent such as dioxane or dichloromethane to provide acompound of Formula IIa. Suitable amine protecting groups are known inthe chemical arts and include t-BOC and Cbz as well as those discussedin T. W. Green, P. G. M. Wuts, “Protective Groups in Organic Synthesis”Wiley-Interscience, New York, 1999.

A compound of Formula IIIa where Pg is a suitable amine protecting groupmay be prepared from a compound of Formula IVa (Scheme 2). Morespecifically, a compound of Formula IVa where Pg is tert-butylcarboxylate is reacted with 3-(chloromethyl)-5-methyl-1,2,4-oxadiazolein the presence of a base such as sodium tert-butoxide to provide acompound of Formula IIIa. The reaction is conveniently carried out in asolvent such as acetonitrile or dimethylformamide. A compound of FormulaIVa where Pg is tert-butyl carboxylate may be prepared essentially asdescribed in WO 2004/094380 A1. More specifically, a compound of FormulaVa is reacted with a reducing agent such as lithiumtri(sec-butyl)borohydride in a solvent such as tetrahydrofuran toprovide a compound of Formula IVa where Pg is tert-butyl carboxylate. Acompound of Formula Va where Pg is a suitable amine protecting group maybe prepared by processes known in the chemical arts including thosedescribed in WO 2004/094380 A1.

Preparation 1 Synthesis of tert-butylN-(4-fluoro-5-formyl-thiazol-2-yl)carbamate

Cesium fluoride (227 g, 1480 mmol) is added to a solution of tert-butylN-(4-chloro-5-formyl-thiazol-2-yl)carbamate (38.8 g, 148 mmol; forpreparation of tert-butyl N-(4-chloro-5-formyl-thiazol-2-yl)carbamatesee for example, N. Masuda, et al., Bioorg Med Chem, 12, 6171-6182(2004)) in DMSO (776 mL) at room temperature. The reaction mixture isstirred in a 145° C. heating block with an internal temperature of 133°C. for 48 hours, then the mixture is cooled in an ice-water bath. To themixture is added saturated aqueous sodium bicarbonate solution (500 mL),brine (500 mL) and ethyl acetate (500 mL). The mixture is stirred atroom temperature for 10 minutes, then is filtered through diatomaceousearth, washing with ethyl acetate (500 mL). The filtrate is transferredto a separating funnel and the layers are separated, then the aqueouslayer is extracted with ethyl acetate (1 L). The combined organics arewashed with brine (1 L), then the brine layer is extracted with ethylacetate (300 mL). The combined organics are dried over sodium sulfate,filtered and concentrated to give a residue. The residue is passedthrough a pad of silica gel (330 g) eluting with 5% ethyl acetate indichloromethane (1.5 L) and the filtrate is concentrated to give aresidue (24.2 g).

The residue (32.7 g of combined lots, 133 mmol) is dissolved inisopropanol (303 mL), filtered and then is purified by SFC(Supercritical Fluid Chromatography) using an IC column (cellulosepolysaccharide derivative: tris (3,5-dichlorophenylcarbamate, 30×250 mm,5 u) with 10% IPA (no additive) at 180 mL/minute with 3 mL injections.The product-containing fractions are concentrated to give the titlecompound (16.1 g. MS m/z 247.0 (M+H).

Preparation 2 Synthesis N-(4-fluoro-5-formyl-thiazol-2-yl)acetamide(Method A)

In a jacketed vessel, zinc bromide (91.9 g, 408 mmol) is added in oneportion to a mixture of tert-butylN-(4-fluoro-5-formyl-thiazol-2-yl)carbamate (33.5 g, 136 mmol) anddichloromethane (503 mL) at room temperature. The reaction mixture isstirred overnight at an internal temperature of 37° C., then the jackettemperature is set to −10° C. and tetrahydrofuran (111 mL) is addeddropwise over 15 minutes, maintaining an internal temperature below 6°C. The jacket temperature is then set to −30° C. and pyridine (110 mL,1360 mmol) is added dropwise over 5 minutes, maintaining an internaltemperature below 5° C. The jacket temperature is set to 0° C. andacetic anhydride (116 mL, 1220 mmol) is added dropwise over 5 minutes.The reaction mixture is stirred overnight at an internal temperature of37° C., then is cooled to room temperature and passed through a shortpad of diatomaceous earth, eluting with tetrahydrofuran (500 mL). Thefiltrate is transferred to a flask and the mixture is concentrated togive a residue, which is concentrated from toluene (50 mL). To theresidue is added a solution of citric acid monohydrate (57.2 g, 272mmol) in water (400 mL) and 2-methyltetrahydrofuran (400 mL) and themixture is stirred at 40° C. for 5 minutes, then is passed through ashort pad of diatomaceous earth, eluting with 2-methyltetrahydrofuran(100 mL). The filtrate is transferred to a separating funnel and thelayers are separated. The aqueous layer is extracted with2-methyltetrahydrofuran (2×250 mL) and the combined organics are dilutedwith water (500 mL). To the mixture is added solid sodium bicarbonateportionwise over 5 minutes with stirring until gas evolution ceases. Themixture is transferred to a separating funnel and the layers areseparated, then the aqueous layer is extracted with2-methyltetrahydrofuran (200 mL and 100 mL). The combined organics aredried over sodium sulfate, filtered and concentrated to give a residue,which is diluted with 2-methyltetrahydrofuran (100 mL) and the mixtureis passed through a short pad of silica gel (250 g), eluting with2-methyltetrahydrofuran (2.5 L). The filtrate is concentrated to give aresidue which is suspended in a 1:1 mixture of dichloromethane andheptane (202 mL). The mixture is stirred at room temperature for 30minutes and then filtered. The filtered solid is dried under vacuum at40° C. for 2 hours to give the title compound (18.0 g, 70%). MS m/z189.0 (M+H).

Alternative Synthesis of N-(4-fluoro-5-formyl-thiazol-2-yl)acetamide(Method B)

Add dichloromethane (1325 g, 15.6 mol) to2-amino-4-chlorothiazole-5-carbaldehyde (100 g, 0.61 mol) and pyridine(194.6 g, 2.46 mol), and cool to 0-5° C. Add acetic anhydride (188.4 g,1.85 mol) dropwise, maintaining the temperature at 0-5° C. Afteraddition is complete, adjust the temperature to 20-25° C. and stir for41 hours. Concentrate under reduced pressure followed by addition of 35%aqueous HCl (200 mL) and water (1.5 L), maintaining the temperature atless than 40° C. Cool to 20-25° C. and stir for 18 hours. Filter themixture and wash the collected solid with water. Dry the solids at60-65° C. for 24 h to provide N-(4-chloro-5-formylthiazol-2-yl)acetamide(75 g, 0.4 mol).

Under an inert atmosphere, add sulfolane (1000 ml) to theN-(4-chloro-5-formylthiazol-2-yl)acetamide (50 g, 0.244 mol, prepareddirectly above), tetramethylammonium chloride (107.1 g, 0.977 mol), andcesium fluoride (370.6 g, 2.44 mmol). Heat to 130° C. and stir for 23 h.HPLC analysis shows 75% conversion with an in situ yield of 45% of thetitle compound.

Alternative Synthesis of N-(4-fluoro-5-formyl-thiazol-2-yl)acetamide(Method C)

Add 2-propanol (150 mL) to tetramethylammonium fluoride.tetrahydrate(10.2 g, 109.0 mmol) and concentrate the mixture to 2-3 volumes undervacuum with internal temperature maintained at 70° C. to remove water.Add 2-propanol (200 mL) and and concentrate the mixture to 2-3 volumesunder vacuum. Repeat two more times. Add DMF (200 mL) and concentrate to2-3 volumes under vacuum. Add THF (200 mL) and concentrate to 2-3volumes. Repeat two more times. ChargeN-(4-chloro-5-formylthiazol-2-yl)acetamide (1.22 g, 5.96 mmol, preparedabove in Method B) and DMF (12 ml). Heat to 110° C. and stir for 12 h.Cool reaction mixture to 25° C. Add 2-methyltetrahydrofuran (40 mL) andwater (40 mL). The layers are separated and the aqueous layer wasextracted with 2-methyltetrahydrofuran (40 mL). The layers wereseparated and the combined organic layers were washed with water (20mL). The layers were separated and the organic layer was concentrated.Add ethyl acetate (20 mL) and water (5 mL). The layers were separatedand the organic layer concentrated to remove solvent. Add ethyl acetate(2 mL) and heptane (2 mL) and filter. The filtered solid is dried undervacuum at 55° C. for 18 hours to give the title compound as a 93%mixture with N-(4-chloro-5-formylthiazol-2-yl)acetamide.

Preparation 3 Synthesis of tert-butyl(2S,4S)-4-hydroxy-2-methyl-piperidine-1-carboxylate

To a flask is added tert-butyl(2S)-2-methyl-4-oxo-piperidine-1-carboxylate (50 g, 234.44 mmol) andtetrahydrofuran (500 mL). The mixture is cooled to −65° C. under anatmosphere of nitrogen and lithium tri(sec-butyl)borohydride (304.77 mL,304.77 mmol; 1M in tetrahydrofuran) is added dropwise over 45 minutes,maintaining an internal temperature below −60° C. The reaction mixtureis stirred at room temperature for 1 hour, then is cooled to −30° C. Tothe reaction mixture is added a mixture of water (25.34 mL) andtetrahydrofuran (100.16 mL), maintaining an internal temperature below−20° C. An aqueous solution of hydrogen peroxide (118.88 mL, 1.17 mol,30 wt/wt %) in water (126.70 mL) is added dropwise over 1 hour,maintaining an internal temperature below 10° C. To the mixture is addedaqueous hydrogen chloride solution (46.89 mL, 234.44 mmol, 5M) andmethyl t-butyl ether (1.00 L) and the mixture is warmed to roomtemperature. The layers are separated and the organic phase is stirredwith a solution of sodium metabisulfite (222.84 g, 1.17 mol) in water(500 mL) for 10 minutes at room temperature. The layers are separatedand the organic phase is dried over magnesium sulfate and concentrated.The residue is purified by flash chromatography (0-50% methyl t-butylether/isohexane, silica gel) and the product-containing fractions arecombined and concentrated to give the title compound (40.4 g, 78%).ES/MS (m/e) 238 (M+Na).

Alternative Synthesis of tert-butyl(2S,4S)-4-hydroxy-2-methyl-piperidine-1-carboxylate

To a glass-lined reactor containing deionized water (460 L), andpotassium dihydrogen phosphate (6.5 kg, 0.41 equiv) at 20° C. is chargedDMSO (27.4 kg, 1.0 vol) and D-(+)-glucose monohydrate (28.9 kg, 1.25equiv). The internal temperature is adjusted to 30° C., and the pH ofthe reaction is adjusted to 6.9 by addition of aqueous sodium hydroxide(8%, 15 L, 0.28 equiv). The reactor is charged with tert-butyl(2S)-2-methyl-4-oxo-piperidine-1-carboxylate (24.9 kg, 1.0 equiv (99.1%ee)), and the mixture is agitated at 30° C. for 15 min. Ketoreductase(KRED-130, 250 g, 1% w/w), glucose dehydrogenase (GDH-101, 250 g, 1%w/w), and NADP sodium salt (63 g, 0.25% w/w) are charged directly to thereaction mixture via an open port. The mixture is maintained at atemperature of 30° C. and pH 7.0±0.2 via addition of 8% aqueous NaHCO₃.After stirring for 16.5 h (99.5% conversion), the reaction is chargedwith Celite™ (12.5 kg, 50 w/w %) and toluene (125 L, 5 vol). Afterstirring for 30 min at 30° C., the mixture is transferred to another2000 L reactor via an in-line GAF-filter (4 sock) over the period of 1h. The mixture is allowed to stand 30 min without agitation, the layersare separated, and the aqueous layer is back-extracted with toluene(2×125 L). The combined organic layers are filtered (in-lineGAF-filter), and the toluene mixture is washed with aqueous sodiumchloride solution (25%, 125 L, 5 vol) at 25° C. The resulting toluenesolution is azeotropically dried (partial vacuum, internal temp <60° C.)to 0.10 w/w % water, and cooled to 20° C. The mixture is filtered out ofthe reactor via a cartridge filter into clean drums under positivenitrogen pressure. The reaction mixture is then transferred from thedrums into a 500 L glass lined vessel and concentrated under vacuum(<60° C.) to a target residual volume of 56 L (2.25 vol). n-Heptane (169kg, 10 vol) is charged at 40° C., and the mixture is seeded with 25 g oftert-butyl (2S,4S)-4-hydroxy-2-methyl-piperidine-1-carboxylate. Theresulting thick slurry is diluted with additional n-heptane (25 L, 1vol) and cooled to 16° C. over 4 h. The product is isolated viacentrifugation, washing with n-heptane (25 L per spin; 4 spinsnecessary), yielding 20.3 kg (81%; >99.9% ee) after drying for 11 h in atray dryer at 30° C. ES/MS (m/e) 238 (M+Na).

Preparation 4 Synthesis of tert-butyl(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]piperidine-1-carboxylate

3-(Chloromethyl)-5-methyl-1,2,4-oxadiazole (43.5 g, 301 mmol) is addedto a solution of tert-butyl(2S,4S)-4-hydroxy-2-methyl-piperidine-1-carboxylate (29.5 g, 137 mmol)in acetonitrile (590 mL) at room temperature. The reaction mixture isstirred in an ice-water bath and sodium tert-butoxide (54.3 g, 548 mmol)is added in portions over 10 minutes, maintaining an internaltemperature below 10° C. The reaction mixture is stirred in an ice-waterbath at an internal temperature of 5° C. for 9 hours, then is warmedslowly to room temperature and is stirred overnight. The reactionmixture is cooled in an ice-water bath and saturated aqueous ammoniumchloride solution (200 mL) is added over 5 minutes, maintaining aninternal temperature below 10° C. during the addition. The mixture isthen diluted with water (100 mL) and warmed to room temperature. Themixture is extracted with methyl tert-butyl ether (2×300 mL) and thecombined organics are washed with brine (300 mL). The combined organicsare dried over sodium sulfate, filtered and concentrated to give aresidue. The residue is passed quickly through a pad of silica gel (300g) eluting with methyl tert-butyl ether (1 L) and the filtrate isconcentrated to give the title compound (46.5 g, 109%). MS m/z 334.0(M+Na).

Alternative Synthesis of tert-butyl(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]piperidine-1-carboxylate

To a solution of tert-butyl(2S,4S)-4-hydroxy-2-methyl-piperidine-1-carboxylate (0.25 g, 1.16 mmol)and 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole (0.308 g, 2.32 mmol) inN,N-dimethylformamide (3 mL) under nitrogen at 0° C. is addedportionwise sodium tert-butoxide (0.35 g, 3.5 mmol) over 5 min. Thereaction mixture is stirred at rt for 10 min then at 40° C. for 12 h.The reaction mixture is cooled to room temperature then quenched withwater (10 mL). The layers are separated and the aqueous phase isextracted with methyl tert-butyl ether (2×10 mL). The combined organicextracts are washed with an aqueous solution of lithium chloride (5%),dried over magnesium sulfate, filtered and concentrated under reducedpressure to afford the title compound (0.49 g, 0.7 mmol, 81% yield, 60%purity) as a brown oil. MS m/z 334.0 (M+Na).

Preparation 5 Synthesis of5-methyl-3-[[(2S,4S)-2-methyl-4-piperidyl]oxymethyl]-1,2,4-oxadiazolehydrochloride

A flask containing tert-butyl(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]piperidine-1-carboxylate(4.03 g, 12.9 mmol) is submerged in an ice-water bath. To this flask isadded a 4M solution of hydrochloric acid in 1,4-dioxane (25.9 mL, 104mmol) dropwise over 5 minutes with stirring, maintaining an internaltemperature below 20° C. during the addition. The reaction mixture isstirred at room temperature for 1 hour, then is concentrated to give thetitle compound (3.56 g, 92% yield based on 83% purity measured by ¹HNMR. MS m/z 212.0 (M+H).

Alternative Synthesis of5-methyl-3-[[(2S,4S)-2-methyl-4-piperidyl]oxymethyl]-1,2,4-oxadiazolehydrochloride

Add methanol (50 mL) to tert-butyl(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]piperidine-1-carboxylate(12.9 g, 0.041 mol). The mixture is cooled to 0° C. A 4M solution ofhydrochloric acid in methanol (80 mL) is added dropwise to the cooledmixture, maintaining an internal temperature below 20° C. The reactionmixture is then stirred at room temperature for 18 hours. The mixture isthen concentrated to remove solvent. Acetone (10 mL) is added and themixture is stirred for 20 min. Tetrahydrofuran (40 mL) is added and themixture is stirred for 3 hours. The solid is collected by filtrationunder nitrogen and the filtered solid cake is rinsed withtetrahydrofuran. The filtered solid is then dried under vacuum at 45° C.for 2 hours to give the title compound as a 90% purity.Recrystallization using acetone can increase purity of title compound to95%.

Preparation 6 Synthesis of5-methyl-3-[[(2S,4S)-2-methyl-4-piperidyl]oxymethyl]-1,2,4-oxadiazole

To a solution of tert-butyl(2S,5S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]piperidine-1-carboxylate(0.49 g, 1.6 mmol) in dichloromethane (10 mL) under nitrogen is addedtrifluoroacetic acid (1.8 mL, 23 mmol). The mixture is stirred at roomtemperature for 3 h. The mixture is concentrated under reduced pressureto afford a yellow oil. The residue is dissolved in methanol (5 mL) andpoured onto a cation exchange cartridge, eluted with methanol (2×10 mL)then a 2M ammonia solution in methanol (10 mL). The filtrate isconcentrated under reduced pressure to give title compound (0.3 g, 1.4mmol, 91%). MS m/z 212.0 (M+H).

EXAMPLE 1 Synthesis ofN-[4-fluoro-5-[[(2S,5S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamide

N-(4-Fluoro-5-formyl-thiazol-2-yl)acetamide (28.3 g, 150 mmol) is addedto 5-methyl-3-[[(2S,4S)-2-methyl-4-piperidyl]oxymethyl]-1,2,4-oxadiazolehydrochloride (48.7 g, 185 mmol, 94% purity) in ethyl acetate (707 mL)at room temperature. The reaction mixture is stirred at room temperatureand N,N-diisopropylethylamine (34.1 mL, 195 mmol) is added dropwise over1 minute, then sodium triacetoxyborohydride (98.5 g, 451 mmol) is addedin one portion. The reaction mixture is stirred in a 31° C. heatingblock overnight with an internal temperature of 30° C., then is cooledin an ice-water bath to an internal temperature of 5° C. To the mixtureis added 2M aqueous hydrochloric acid solution (226 mL) over 15 minutes,maintaining an internal temperature below 10° C. To the mixture is addedwater (250 mL) and the mixture is stirred at room temperature for 5minutes. The layers are separated and the organic layer is extractedwith a mixture of 2M aqueous hydrochloric acid solution (28 mL) in water(50 mL). The first aqueous layer is stirred in an ice-water bath and 50%aqueous sodium hydroxide solution (25.7 mL) is added dropwise over 10minutes, maintaining an internal temperature below 10° C. The mixture isdiluted with saturated aqueous sodium bicarbonate solution (100 mL),then is stirred at room temperature for 10 minutes and then is extractedwith ethyl acetate (3×400 mL). The combined organics are dried oversodium sulfate, filtered and concentrated to give a residue. The secondaqueous layer from the extraction with aqueous hydrochloric acid isdiluted with 2-methyltetrahydrofuran (200 mL) and the mixture is passedthrough a short pad of diatomaceous earth. The filtrate is transferredto a separating funnel and the layers are separated. The aqueous layeris stirred in an ice-water bath and 50% aqueous sodium hydroxidesolution (3.15 mL) is added dropwise over 5 minutes, maintaining aninternal temperature below 10° C. The mixture is diluted with saturatedaqueous sodium bicarbonate solution (10 mL), then is stirred at roomtemperature for 5 minutes and then is extracted with ethyl acetate (3×40mL) and 10% isopropanol in ethyl acetate (100 mL). The combined organicsare dried over sodium sulfate, filtered and concentrated to give aresidue, which is combined with the residue from the first part of theworkup. The combined residue is passed through a pad of silica gel (350g) eluting with ethyl acetate (3.5 L) and the filtrate is concentratedto give a residue (45.8 g).

The residue (47.5 g of combined lots, 123.9 mmol) is purified by flashchromatography, eluting with 50-100% ethyl acetate in heptane. Theproduct-containing fractions are concentrated to residue, which issuspended in a 1:1 mixture of methyl-tert-butyl ether and heptane (448mL). The mixture is stirred in a 46° C. heating block for 30 minutes atan internal temperature of 45° C., then is cooled to room temperatureover 2 hours with stirring. The mixture is filtered, washing the solidwith a 1:1 mixture of methyl-tert-butyl ether and heptane (30 mL). Thefiltered solid is dried under vacuum at 40° C. overnight to give thetitle compound (28.5 g). MS m/z 384.0 (M+H); [α]_(D) ²⁰=+33.4° (C=0.26,methanol).

Alternative Synthesis ofN-[4-fluoro-5-[[(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamide

To a solution of N-(4-fluoro-5-formyl-thiazol-2-yl)acetamide (0.05 g,0.28 mmol) and5-methyl-3-[[(2S,4S)-2-methyl-4-piperidyl]oxymethyl]-1,2,4-oxadiazole(0.04 g, 0.19 mmol) in dichloromethane (10 mL) under nitrogen are addedN,N-diisopropylethylamine (0.1 mL, 0.57 mmol) and sodiumtriacetoxyborohydride (0.12 g, 0.57 mmol). The reaction mixture isstirred at room temperature for 12 h. The reaction mixture is pouredinto a saturated aqueous solution of sodium bicarbonate (10 mL). Thelayers are separated and the aqueous phase is extracted withdichloromethane (2×10 mL). The combined organic extracts are dried overmagnesium sulfate, filtered and concentrated under reduced pressure toafford an orange oil.

The residue is taken up in methanol (to a total volume of 9.8 ml),filtered and purified by prep-HPLC (Phenomenex Gemini-NX 10 Micron50*150 mm C-18) (CH₃CN & Water with 10 mM ammonium bicarbonate adjustedto pH 9 with ammonium hydroxide, 15% to 100% CH₃CN over 10 min at 110ml/min) (1 injection) (271/204 nm) to give the title compound (0.02 g,0.05 mmol, 28%). MS m/z 384.2 (M+H).

EXAMPLE 1A CrystallineN-[4-fluoro-5-[[(2S,5S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamide

Suspend crudeN-[4-fluoro-5-[[(2S,5S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamide(29.9 g) in 448 mL of 50% methyl tert butyl ether in heptane at 46° C.for 30 minutes. Stir the mixture and cool to 19° C. over two hoursbefore filtering following with a wash of 30 mL of 50% methyl tert butylether in heptane to provide the title compound (28.5 g, 95% yield).

X-Ray Powder Diffraction (XRPD) of Example 1A

The XRPD patterns of crystalline solids are obtained on a Bruker D4Endeavor X-ray powder diffractometer, equipped with a CuKa source(λ=1.54060 Å) and a Vantec detector, operating at 35 kV and 50 mA. Thesample is scanned between 4 and 40° in 2θ, with a step size of 0.0087°in 2θ and a scan rate of 0.5 seconds/step, and with 0.6 mm divergence,5.28 mm fixed anti-scatter, and 9.5 mm detector slits. The dry powder ispacked on a quartz sample holder and a smooth surface is obtained usinga glass slide. It is well known in the crystallography art that, for anygiven crystal form, the relative intensities of the diffraction peaksmay vary due to preferred orientation resulting from factors such ascrystal morphology and habit. Where the effects of preferred orientationare present, peak intensities are altered, but the characteristic peakpositions of the polymorph are unchanged. (see, e.g. The U. S.Pharmacopeia 38-National Formulary 35 Chapter 941 Characterization ofcrystalline and partially crystalline solids by X-ray powder diffraction(XRPD) Official May 1, 2015). Furthermore, it is also well known in thecrystallography art that for any given crystal form the angular peakpositions may vary slightly. For example, peak positions can shift dueto a variation in the temperature or humidity at which a sample isanalyzed, sample displacement, or the presence or absence of an internalstandard. In the present case, a peak position variability of ±0.2 in 2θwill take into account these potential variations without hindering theunequivocal identification of the indicated crystal form. Confirmationof a crystal form may be made based on any unique combination ofdistinguishing peaks (in units of ° 2θ), typically the more prominentpeaks. The crystal form diffraction patterns, collected at ambienttemperature and relative humidity, aree adjusted based on NIST 675standard peaks at 8.85 and 26.77 degrees 2-theta.

A prepared sample of crystallineN-[4-fluoro-5-[[(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamideis characterized by an XRPD pattern using CuKa radiation as havingdiffraction peaks (2-theta values) as described in Table 1 below.Specifically the pattern contains a peak at 12.1° in combination withone or more peaks selected from the group consisting of 15.3°, 21.6°,22.2°, 22.7°, 23.5°, 24.3°, and 26.8° with a tolerance for thediffraction angles of 0.2 degrees.

TABLE 1 X-ray powder diffraction peaks of crystalline N-[4-fluoro-5-[[(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamide, Example 1A.Relative Intensity Peak Angle (2-Theta °) +/− 0.2° (% of most intensepeak) 1 7.7 9 2 10.1 9 3 12.1 100 4 15.3 50 5 18.3 11 6 19.3 13 7 21.616 8 22.2 16 9 22.7 16 10 23.5 30 11 24.3 35 12 26.8 27

In Vitro Human OGA Enzyme Assay

Generation of OGA Proteins

The nucleotide sequence encoding full-length humanO-GlcNAc-β-N-acetylglucosaminidase (NM_012215) is inserted intopFastBac1 (Invitrogen) vector with an N-terminal poly-histidine (HIS)tag. Baculovirus generation is carried out according to the Bac-to-BacBaculovirus Expression system (Invitrogen) protocol. Sf9 cells areinfected at 1.5×10⁶ cells/mL using 10 mL of P1 virus per Liter ofculture and incubated at 28° C. for 48 hrs. Cells are spun down, rinsedwith PBS and the pellets stored at −80° C. The above OGA protein(His-OGA) is purified as follows: 4 L of cells are lysed in 200 mL ofbuffer containing 50 mM Tris, pH 8.0, 300 mM NaCl, 10% glycerol, 10 mMImidazol, 1 mM Dithiothreitol (DTT), 0.1% Triton™ X-100, 4 tablets ofprotease inhibitors (complete EDTA-Free, Roche) for 45 min at 4° C. Thiscell lysate is then spun for 40 min at 16500 rpm at 4° C., andsupernatant incubated with 6 mL of Ni-NTA resin (nickel-nitrilotriaceticacid) for 2 hours at 4° C.

Resin is then packed onto column and washed with 50 mM Tris, pH 8.0, 300mM NaCl, 10% glycerol, 10 mM Imidazole, 0.1% Triton™ X-100, 1 mM DTT,followed by 50 mM Tris, pH 8.0, 150 mM NaCl, 10 mM Imidazol, 10%glycerol, 1 mM DTT. The proteins are eluted with 50 mM Tris, pH 8.0, 150mM NaCl, 300 mM Imidazole, 10% glycerol, 1 mM DTT. Pooled His-OGAcontaining fractions are concentrated to 6 ml and loaded onto Superdex75(16/60). The protein is eluted with 50 mM Tris, pH 8.0, 150 mM NaCl, 10%glycerol, 2 mM DTT. Fractions containing His-OGA are pooled and proteinconcentration measured with BCA (Bradford Colorimetric Assay).

OGA Enzyme Assay

The OGA enzyme catalyses the removal of O-GlcNAc from nucleocytoplasmicproteins. To measure this activity Fluoresceindi-N-acetyl-β-N-acetyl-D-glucosaminide (FD-GlcNAc, Kim, Eun Ju; Kang,Dae Ook; Love, Dona C.; Hanover, John A. Carbohydrate Research (2006),341(8), 971-982) is used as a substrate at a final concentration of 10μM (in the 96 well assay format) or 6.7 μM (in the 384 well assayformat). This fluorogenic substrate becomes fluorescent upon cleavage byOGA, so that the enzyme activity can be measured by the increase influorescence detected at 535 nm (excitation at 485 nm).

The assay buffer is prepared to give a final concentration of 50 mMH₂NaPO₃—HNa₂PO₃, 0.01% bovine serum albumin and 0.01% Triton™ X-100 inwater, at pH 7. The final enzyme concentration is 3 nM (in the 96 wellassay format) or 3.24 nM (in the 384 well assay format). Both assayformats yield essentially equivalent results.

Compounds to be tested are diluted in pure dimethyl sulfoxide (DMSO)using ten point concentration response curves. Maximal compoundconcentration in the reaction mixture is 30 μM. Compounds at theappropriate concentration are pre-incubated with OGA enzyme for 30minutes before the reaction is started by the addition of substrate.Reactions are allowed to proceed for 60 minutes at room temperature.Then, without stopping the reaction, fluorescence is read. IC₅₀ valuesare calculated by plotting the normalized data vs. log of the compoundand fitting the data using a four parameter logistic equation.

The compound of Example 1 was tested essentially as described above andexhibited an IC₅₀ of 2.36 nM±0.786 (n=8). This data demonstrates thatthe compound of Example 1 inhibits OGA enzyme activity in vitro.

Whole Cell Assay for Measuring the Inhibition of OGA Enzyme Activity

Cell Plating:

Utilizing standard conditions known in the art, TRex-293 cells modifiedfor inducible expression of the P301S-1N4R form of the microtubuleassociated protein tau are generated and maintained in growth media,consisting of DMEM High Glucose (Sigma# D5796), supplemented with 10%Tetracyclin-free Fetal Bovine Serum (FBS, Sigma F2442), 20 mM HEPES, 5μg/mL Blasticidin (Life Technologies# A11139-03) and 200 μg/mL Zeocin(Life Technologies# R250-01). For the experiments, cells are plated ingrowth media at 10,000-14,000 cells per well in a Corning Biocoat(356663) 384 well plate coated with poly-D-Lysine, and incubated 20-24 hin a cell incubator at 37° C./5% CO₂. Experiments are performed withoutinducing Tau expression.

Compound Treatment:

Compounds to be tested are serially diluted 1/3 in pure DMSO using tenpoint concentration response curves and further diluted in growth media.20-24 h after plating, cells are treated with test compound in growthmedia; maximal compound concentration is 15 μM (0.15% DMSO). The maximuminhibition is defined by replicate measurements of 15 uM Thiamet G andthe minimum inhibition is defined by replicate measurements of 0.15%DMSO treatment. The cells are returned to the incubator at 37° C./5% CO₂for 20-24 hours. Compounds are tested in duplicates within each plate.

Immunostaining:

After 20-24 hours of compound treatment, the media is removed from theassay plate and 25 μL of 3.7% Formaldehyde solution (Sigma # F1635) inDPBS (Sigma #D8537) are added to each well and incubated for 30 minutes.The cells are then washed once with DPBS and then permeabilized with0.1% Triton™ X-100 (Sigma# T9284). After 30 minutes, cells are washedtwice with DPBS and then blocking solution (1% BSA/DPBS/0.1% Triton™X-100) is added to each well and incubated for 60 minutes. The blockingsolution is removed and a 0.40-0.33 μg/mL solution of O-GlcNAc Proteinantibody (RL2 clone, Thermo, MA1072) in blocking solution is added tothe cells and allowed to sit overnight at 2-8° C. The next day, thecells are washed twice with DPBS and the secondary antibody, Alexa Fluor488 goat anti-mouse IgG (Life Technologies # A11001) at 2 ug/mL in DPBSis added to each well and allowed to sit at room temperature for 90 min.The secondary antibody is removed, cells washed twice with DPBS and asolution of DAPI (Sigma #D9564) and RNase (Sigma, R6513) in DPBS at aconcentration of 1 and 50 ug/mL, respectively, is added to each well.The plate is sealed, incubated for one hour and analyzed on an AcumeneX3 hci (TTP Labtech). All the incubations and washing steps describedabove are done at room temperature, except for the primary antibody.

Analysis and Results:

The plates are analyzed on an Acumen eX3 instrument using a 488 and 405nm excitation lasers and two emission filters FL2 (500-530 nm) and FL1(420-490 nm). The FL2 filter is the signal corresponding to the O-GlcNAcProtein antibody (RL2 clone) and the FL1 filter is the signalcorresponding to the cell nuclei (DAPI). The ratio Total FL2/Total FL1(Total fluorescence of each well without object or population selection)is used for data analysis. The data is normalized to a maximuminhibition as referenced by a 15 μM treatment of Thiamet G and a minimuminhibition as achieved by a 0.15% DMSO treatment. The data is fittedwith a non-linear curve fitting application (4-parameters logisticequation) and IC₅₀ values are calculated and reported.

The compound of Example 1 was tested essentially as described above andexhibited an IC₅₀ of 21.9 nM±7.3 (n=5). This data demonstrates that thecompound of Example 1 inhibits OGA enzyme activity in a cellular assay.

We claim:
 1. A compound of the formula:

or a pharmaceutically acceptable salt thereof.
 2. The compound or saltaccording to claim 1 wherein the methyl at position 2 is in the cisconfiguration relative to the oxygen at position 4 on the piperidinering:


3. The compound or salt according to claim 2 wherein the compound isN-[4-fluoro-5-[[(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamide.4. The compound according to claim 3 which isN-[4-fluoro-5-[[(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamide.5. The compound according to claim 4 wherein the compound iscrystalline.
 6. The compound according to claim 5 which is characterizedby a peak in the X-ray powder diffraction spectrum, at diffraction angle2-theta of 12.1° in combination with one or more peaks selected from thegroup consisting of 15.3°, 21.6°, 22.2°, 22.7°, 23.5°, 24.3°, and 26.8°,with a tolerance for the diffraction angles of 0.2 degrees.
 7. Apharmaceutical composition, comprising a compound or a pharmaceuticallyacceptable salt thereof according to claim 1 with one or morepharmaceutically acceptable carriers, diluents, or excipients.
 8. Aprocess for preparing a pharmaceutical composition, comprising admixinga compound or a pharmaceutically acceptable salt thereof according toclaim 1 with one or more pharmaceutically acceptable carriers, diluents,or excipients.
 9. A pharmaceutical composition, comprising a compound ora pharmaceutically acceptable salt thereof according to claim 3 with oneor more pharmaceutically acceptable carriers, diluents, or excipients.10. A process for preparing a pharmaceutical composition, comprisingadmixing a compound or a pharmaceutically acceptable salt thereofaccording to claim 3 with one or more pharmaceutically acceptablecarriers, diluents, or excipients.